Method and device for preparing a medical fluid

ABSTRACT

A method for extracorporeal treatment of blood includes preparing a treatment liquid from a liquid and two concentrated solutions by circulating the liquid in a preparation conduit at a flowrate Q 0 ; injecting a first concentrated solution containing at least a first ionic substance A and a second ionic substance B into the preparation conduit at a flowrate Q 1 ; and injecting a second concentrated solution containing at least the first ionic substance A into the preparation conduit at a flowrate Q 2 . The ionic substance B may have a first concentration in the first concentrated solution and a second concentration, different from the first concentration, in the second concentrated solution. The method may also include regulating the injection flowrates Q 1  and Q 2  in such a way that at any given time the diluted solution resulting from the mixing of the liquid and the concentrated solutions has a desired concentration of the first ionic substance A and a desired concentration of the second ionic substance B. The method may further include supplying the treatment liquid to an inlet of a membrane exchanger; removing a spent liquid from an outlet of the membrane exchanger; measuring the concentration of the second ionic substance in the treatment liquid; and measuring the concentration of the second ionic substance in the spent liquid. The injection flowrates Q 1  and Q 2  may be regulated on the basis of the concentrations of the second ionic substance measured in the treatment liquid and in the spent liquid.

The present invention relates to a method and a device for preparing amedical liquid.

The invention has an application in particular in the treatment of renalinsufficiency, where it can be used for preparing a dialysis liquid. Inthis context, the invention is particularly suitable for treatingpatients whose internal medium presents an excess of potassium.

The kidneys perform many functions, including elimination of water,excretion of catabolites (or waste products of metabolism, such as ureaand creatinine), regulation of the concentration of electrolytes in theblood (sodium, potassium, magnesium, calcium, bicarbonates, phosphates,chlorides), and regulation of the acid-base balance of the internalmedium, which balance is obtained in particular through the eliminationof weak acids (phosphates, monosodium acids) and through the productionof ammonium salts.

In persons who have lost the use of their kidneys, since these excretoryand regulatory mechanisms no longer function, the internal mediumbecomes charged with water and waste products of metabolism and presentsan excess of electrolytes (sodium in particular), and, in general,acidosis, with the pH of the blood plasma shifting towards 7.

To remedy kidney dysfunction, the conventional practice is to treat theblood by extracorporeal circulation in a semipermeable membraneexchanger (hemodialyzer), with circulation, on either side of themembrane, of the patient's blood and of a dialysis liquid comprising themain electrolytes of the blood (chlorides, bicarbonates, sodium,calcium, potassium, magnesium) in concentrations close to those of theblood of a healthy subject. As a result of the physical phenomenoncalled dialysis, the molecules migrate from the liquid in which theirconcentration is highest to the liquid in which their concentration islowest.

A significant electrolytic change in uremic patients is the increase inthe potassium concentration of the plasma. Now, hyperkalemia (too high aconcentration of potassium) is associated with incidents linked tohyperpolarization of the membrane of the neuromuscular cells, which canresult in hypokinetic arrhythmia and complete atrioventricular block.One of the objectives of dialysis treatment is therefore to eliminatethe excess potassium accumulated by the patients between two treatmentsessions. In accordance with the physical principle cited above, thequantity of potassium eliminated during treatment depends directly onthe difference between the concentration of the potassium in the plasmaand the concentration of the potassium in the dialysis liquid, which isgenerally fixed at a constant level, less (approximately 2 mEq/l) thanthe physiological level (approximately 3.5 mEq/l).

At the start of conventional dialysis treatment, a patient withhyperkalemia (whose plasma potassium concentration can be as high as 10mEq/l) is exposed to the undesirable effects resulting from theconsiderable difference between the potassium concentration of hisplasma and that of the dialysis liquid: this increased gradient in factcauses a substantial diffusive flow of potassium across the membrane ofthe hemodialyzer, which in turn causes a substantial flow of potassiumacross the membrane of the cells, which affects the electric potentialof the membrane at rest and, consequently, the cellular excitability. Asthis mechanism also influences the cardiac pacemaker cells, the patentruns the risk of cardiac arrhythmia during the dialysis treatment. Thisphenomenon is naturally heightened in cases of cardiac weakness and canlead to a reduction in the ejection volume affecting the cardiovascularcirculation.

A particular object of the invention is therefore to modify theconditions of conventional dialysis treatment, without however affectingits effectiveness, in such a way that patients with hyperkalemia are nolonger exposed to the risks mentioned above.

A general object of the invention is to conceive a device and a methodfor preparing a treatment liquid which can be used for extracorporealtreatment of blood, and by means of which the concentration of two ionicsubstances can be adjusted separately, in particular sodium andpotassium (or calcium, or magnesium).

According to the invention, this object is achieved by means of a methodfor preparing a medical liquid from a liquid, such as water, and twoconcentrated solutions, comprising the following steps:

circulating the liquid in a conduit, at a flowrate Q0;

injecting into the conduit, at a flowrate Q1, a first concentratedsolution containing a first ionic substance A and a second ionicsubstance B, the ionic substances A and B having, respectively, in thefirst concentrated solution, a concentration [Asol] and a firstconcentration [B1sol];

injecting into the conduit, at a flowrate Q2, a second concentratedsolution containing the first ionic substance A and the second ionicsubstance B, the first ionic substance A having, in the secondconcentrated solution, the same concentration [Asol] as in the firstconcentrated solution, and the second ionic substance B having, in thesecond concentrated solution, a second concentration [B2sol] differentthan the first concentration [B1sol] in the first concentrated solution;

regulating the injection flowrate Q1 and the injection flowrate Q2 ofthe first and second concentrated solutions in such a way that at anygiven time the diluted solution resulting from the mixing of the liquidand the concentrated solutions has a desired concentration [Ades] offirst substance A and a desired concentration [Bdes] of second substanceB.

According to one characteristic of the invention, the injection flowrateQ1 and the injection flowrate Q2 of the concentrated solutions A and Bare varied over the course of time in such a way that the concentrationof the second substance B in the diluted solution varies over the courseof time in accordance with a predetermined profile.

According to another characteristic of the invention, the flowrate Q0 ofthe liquid in the conduit is constant, and the sum of the injectionflowrates Q1+Q2 of the concentrated solutions A and B is maintainedconstant in such a way that the concentration of the first substance Ain the diluted solution remains substantially constant.

According to yet another characteristic of the invention, the injectionflowrate Q1 and the injection flowrate Q2 of the concentrated solutionsA and B are varied over the course of time in such a way that theconcentration of the first substance A in the diluted solution variesover the course of time in accordance with a predetermined profile.

The invention also relates to a device for preparing a treatment liquidfrom a liquid, such as water, and two concentrated solutions,comprising:

a conduit with a first end intended to be connected to a source ofliquid, such as water, and a second end for delivering a treatmentliquid;

first injection means for injecting into the conduit, at a flowrate Q1,a first concentrated solution containing a first ionic substance A and asecond ionic substance B, the ionic substances A and B having,respectively, in the first concentrated solution, a concentration [Asol]and a first concentration [B1sol];

second injection means for injecting into the conduit, at a flowrate Q2,a second concentrated solution containing the first ionic substance Aand the second ionic substance B, the first ionic substance A having, inthe second concentrated solution, the same concentration [Asol] as inthe first concentrated solution, and the second ionic substance Bhaving, in the second concentrated solution, a second concentration[B2sol] different than the first concentration [B1sol] in the firstconcentrated solution;

regulating means for regulating the first and second injection means andfor adjusting the injection flowrate Q1 and the injection flowrate Q2 ofthe first and second concentrated solutions in such a way that at anygiven time the diluted solution resulting from the mixing of the liquidand the concentrated solutions has a desired concentration [Ades] offirst substance A and a desired concentration [Bdes] of second substanceB.

In one embodiment of the invention, the device for preparing treatmentliquid is incorporated in a hemodialysis system, the substance A issodium and the substance B is potassium, calcium, or magnesium. As thesodium concentration in a dialysis liquid is much higher than thepotassium (calcium or magnesium) concentration, the potassiumconcentration can be very precisely regulated by measuring theconductivity of the mixture forming in the conduit immediatelydownstream of the site of injection of the first concentrated solutioninto the conduit, and of the mixture forming in the conduit immediatelydownstream of the site of injection of the second concentrated solutioninto the conduit (there is an excellent correlation between theconductivity of a solution and its sodium concentration).

Moreover, there is no danger of influencing the plasma potassium orcalcium concentration of a patient using a very dilute dialysis solutionprepared and administered by a system equipped with reliable means formeasuring concentrations, which would not be the case if this objectivewere achieved by injection of more concentrated solution.

The invention also relates to a kit of solutions for extracorporealtreatment of blood, comprising two concentrated solutions and a bag withtwo compartments intended to contain each of the solutions from the kit.Each of the solutions contains at least two ionic substances A and B,the ionic substance A having the same concentration in the two solutionsand the ionic substance B having different concentrations in twosolutions.

According to one characteristic of the invention, the two solutions areidentical except for one ionic substance whose concentration differsfrom one solution to the other.

Other characteristics and advantages of the invention will become moreapparent on reading the following description. Reference will be made tothe attached drawings, in which:

FIG. 1 is a diagram showing a device for treatment of blood;

FIG. 2 shows a bag with two compartments for containing the twoconcentrated solutions from a treatment kit; and

FIG. 3 is a graph showing several profiles of variation in the potassiumconcentration of a dialysis liquid.

The hemodialysis system shown in FIG. 1 comprises a hemodialyzer 1 withtwo compartments 2, 3 separated by a semipermeable membrane 4. A firstcompartment 2 has an inlet connected to a blood withdrawal conduit 5 onwhich a circulation pump 6 is arranged, and an outlet connected to ablood return conduit 7 on which a bubble trap 8 is interposed.

An infusion device comprising a pump 10 and a balance 11 is provided forinjecting into the bubble trap 8 the contents of a bag 9 of infusionliquid containing sodium bicarbonate. The bag 9 is suspended from thebalance 11 and it is connected to the bubble trap 8 via a conduit 12 onwhich the infusion pump 10 is arranged. The balance 11 serves to controlthe pump 10 so that the flowrate of the infusion liquid is equal to areference flowrate.

The second compartment 3 of the hemodialyzer 1 has an inlet connected toa conduit 12 for supply of fresh dialysis liquid, and an outletconnected to a conduit 13 for removal of spent liquid (dialysis liquidand ultrafiltrate).

The supply conduit 12 connects the hemodialyzer 1 to a device 14 forpreparing dialysis liquid, comprising a main conduit 15 whose upstreamend is intended to be connected to a source of running water. First andsecond subsidiary channels 16, 17 are connected to this main conduit 15.

According to the invention, the free end of the first subsidiary conduit16 is intended to be immersed in a container 18 for a first concentratedsaline solution containing sodium chloride, calcium chloride, magnesiumchloride and potassium chloride. This first conduit 16 is equipped witha pump 19 for metering the first concentrated solution into the dialysisliquid, which is controlled as a function of the comparison between 1) afirst reference value of conductivity for the solution forming at thejunction of the main conduit 15 and the first subsidiary conduit 16, and2) the value of the conductivity of this solution measured by means of afirst conductivity probe 20 arranged on the main conduit 15 immediatelydownstream of the junction between the main conduit 15 and the firstsubsidiary conduit 16.

According to the invention, the free end of the second subsidiaryconduit 17 is intended to be immersed in a container 21 for a secondconcentrated saline solution containing sodium chloride, calciumchloride, magnesium chloride and potassium chloride. This secondsolution contains the same ionic substances as the first solution and inthe same concentrations, except for potassium whose concentration isdifferent. The second conduit 17 is equipped with a pump 22 for meteringthe second concentrated solution into the dialysis liquid, which iscontrolled as a function of the comparison between 1) a second referencevalue of conductivity for the solution forming at the junction of themain conduit 15 and the second subsidiary conduit 17, and 2) the valueof the conductivity of this solution measured by means of a secondconductivity probe 23 arranged on the main conduit 15 immediatelydownstream of the junction between the main conduit 15 and the secondsubsidiary conduit 17.

The conduit 12 for supply of dialysis liquid forms the continuation ofthe main conduit 15 of the device 14 for preparation of dialysis liquid.Arranged on this supply conduit 12, in the direction of circulation ofthe liquid, are a first flowmeter 24 and a first circulation pump 25.

The downstream end of the conduit 13 for removal of spent liquid isintended to be connected to the drain. Arranged on this conduit, in thedirection of circulation of the liquid, are a probe 26 for measuring thepotassium concentration, a second circulation pump 27, and a secondflowmeter 28. An extraction pump 29 is connected to the removal conduit13 upstream of the second circulation pump 27.

The hemodialysis system represented in FIG. 1 also comprises acalculation and control unit 30. This unit is connected to a screen 31and to a keyboard 32 via which the user inputs various reference values:flowrate reference values (blood flowrate Qb, dialysis liquid flowrateQd, infusion solution flowrate Qinf), reference values for concentrationof ionic substances in the dialysis liquid, reference value for theduration of treatment T, reference value for loss of weight WL.Moreover, the calculation and control unit 30 receives informationemitted by the measurement elements of the system, such as theflowmeters 24, 28, the conductivity probes 20, 23, and the probe 26 formeasuring potassium concentration. As a function of the instructionsreceived and of programmed operating modes and algorithms, it controlsthe drive elements of the system, such as the pumps 6, 10, 19, 22, 25,27, 29.

According to the invention, the concentration of sodium and theconcentration of potassium in the dialysis liquid can be adjustedindependently of one another: for a constant flowrate Q0 of water, theconcentration of sodium depends on the sum of the flowrate Q1 of thefirst concentrated solution injected via the pump 19 into the mainconduit 15 and the flowrate Q2 of the second concentrated solutioninjected via the pump 22 into the main conduit 15, while theconcentration of potassium depends on the ratio of the flowrates Q1, Q2of the first and second concentrated solutions. The concentration ofsodium and of potassium in the dialysis liquid is chosen as a functionof each individual patient. It can be set at a fixed value. According tothe invention, for patients with hyperkalemia, the potassiumconcentration of the dialysis liquid is modified continuously during thetreatment session according to a predetermined profile of variation.

Example

The hemodialysis system described above is equipped with a bag 50 madeof flexible transparent plastic, as is represented in FIG. 2, andcomprising two compartments 51 and 52 corresponding respectively to thecontainers 18 and 21 in FIG. 1. The bag 50 is provided in its upper partwith eyelets 53 by which it can be suspended vertically from a suitablesupport. Each compartment 51, 52 is equipped at its base with an accesstube 54, 55 provided at its end with a connection element 56, 57intended to cooperate with a complementary connection element fixed tothe end of the subsidiary conduits 16, 17 of the device 14 forpreparation of dialysis liquid. A clip 58, 59 is arranged on each of thetubes 54, 55.

The compartment 51 (container 18) contains the following substances, inthe following concentrations:

NaCl: 284.31g/l

KCl: 19.57 g/l

CaCl2: 10.29 g/l

MgCl2: 2.63 g/l

Anhydrous glucose: 35 g/l.

The compartment 52 (container 21) contains the following substances, inthe following concentrations:

NaCl: 284.31 g/l

KCl: 0 g/l

CaCl2: 10.29 g/l

MgCl2: 2.63 g/l

Anhydrous glucose: 35 g/l.

By means of these two solutions it is possible, according to theinvention, to prepare a dialysis liquid having a sodium concentration ofbetween approximately 130 mEq/l and approximately 155 mEq/l, and apotassium concentration varying, during a treatment session, frombetween an initial value of approximately 2.5 mEq/l and approximately5.5 mEq/l and a final value of between approximately 1 mEq/l andapproximately 2 mEq/l.

FIG. 3 shows four profiles of variation of the potassium concentrationof a dialysis liquid, which profiles can be obtained using the device 14for preparation of dialysis liquid connected to the bag 50 with twocompartments containing the concentrated solutions which have just beendescribed. In this figure, the broken line shows the constant potassiumconcentration of a conventional dialysis liquid, that is to say 2 mEq/l.

The hemodialysis apparatus which has just been described functions inthe following manner.

An operator inputs to the control unit 30, via the keyboard 32,conventional reference values corresponding to the various parameters oftreatment (prescription), namely the blood flowrate Qb, the dialysisliquid flowrate Qd, the infusion flowrate Qinf of the bicarbonatesolution, the total weight loss WL (quantity of plasma water to bewithdrawn from patient by ultrafiltration), the total duration T of thesession, and the sodium concentration of the dialysis liquid.

According to the invention, the operator also inputs, to the controlunit, an information item or a series of information items concerningthe potassium concentration of the dialysis liquid, which can be eithera fixed reference value or one of the variation profiles storedbeforehand in the control unit, corresponding for example to one of thegraphs in FIG. 3. The operator can also create and store a profileappropriate to an individual client.

According to an alternative embodiment of the invention, the potassiumconcentration of the dialysis liquid is adjusted via the control unit 30in the following manner: a dialysis liquid having a potassiumconcentration corresponding to a predetermined reference value isinitially circulated in the hemodialyzer 1, and this reference value iscompared with the value of the potassium concentration in the spentliquid, measured by the probe 26. The control unit 30 subsequentlycontrols the pumps 19, 22 of the device 14 for preparation of treatmentliquid in such a way that the difference between the reference value andthe measured value remains substantially equal to a given value,corresponding to a difference, acceptable for the patient, between thepotassium concentration of the plasma and that of the dialysis liquid.

After a kit of concentrated solutions, such as the bag described above,has been connected to the conduits 16, 17 of the device 14 forpreparation of dialysis liquid, the dialysis liquid circuit is filledwith dialysis liquid. To do this, the main conduit 15 is connected to asource of running water and the pumps 19, 22, 25, 27 are started up. Thepumps 19 and 22 are regulated via the control unit 30 in such a way thatthe potassium concentration and the sodium concentration of the dialysisliquid are equal to the corresponding reference values. The pumps 25, 27for circulating dialysis liquid are regulated via the control unit 30 insuch a way that the flowrate of the pump 25 situated upstream of thehemodialyzer 1 is equal to the reference flowrate Qd (500 ml/min, forexample) and so that the flowrate of the pump 27 situated downstream ofthe hemodialyzer 1 is such that the flowrates measured by the flowmeters24, 28 are equal.

At the same time as the dialysis liquid circuit is filling with thedialysis liquid according to the prescription, the circuit forextracorporeal blood circulation is rinsed and filled with sterilephysiological liquid.

When priming of the dialysis liquid circuit and of the blood circuit iscompleted, the blood circuit is connected to the patient and thetreatment proper can commence: the pumps 19, 22 of the device 14 forpreparation of dialysis liquid, and the pumps 25, 27 for circulating thedialysis liquid, continue functioning, while the blood pump 6, theextraction pump 29 and the infusion pump 10 are started up. The bloodpump 6 is set at the reference flowrate Qb (for example 200 ml/mn), theinfusion pump 10 is set at the reference flowrate Qinf, and theextraction pump 29 is set at a flowrate QUF calculated by the controlunit 30 on the basis of the reference values for total weight loss WL,infusion flowrate Qinf and total duration of treatment T.

The invention which has just been described is open to variants.

In the same way as the potassium concentration, the calcium or magnesiumconcentration can be adjusted to the needs of each individual patient.

With the preparation device according to the invention, it is possibleto simultaneously adjust the potassium concentration of a dialysisliquid according to a first defined variation profile and the sodiumconcentration of the same dialysis liquid according to a second definedvariation profile.

A probe for measuring the potassium concentration can be mounted on thesupply conduit 12 in order to provide a measured value of the potassiumconcentration which will be used, for example, to calculate thedifference between this value and the value measured downstream of thehemodialyzer 1 by the probe 26.

What is claimed is:
 1. Method for extracorporeal treatment of bloodcomprising the following steps: preparing a treatment liquid from aliquid, such as water, and two concentrated solutions, comprising thefollowing steps: circulating the liquid in a preparation conduit, at aflowrate Q0, injecting into the preparation conduit, at a flowrate Q1, afirst concentrated solution containing at least a first ionic substanceA and a second ionic substance B, the ionic substance B having, in thefirst concentrated solution, a first concentration, injecting into thepreparation conduit, at a flowrate Q2, a second concentrated solutioncontaining at least the first ionic substance A, the second ionicsubstance B having, in the second concentrated solution, a secondconcentration [B2sol] different than the first concentration [B1sol] inthe first concentrated solution, and regulating the injection flowrateQ1 of the first concentrated solution and the injection flowrate Q2 ofthe second concentrated solution in such a way that at any given timethe diluted solution resulting from the mixing of the liquid and theconcentrated solutions has a desired concentration [Ades] of the firstionic substance A and a desired concentration [Bdes] of the second ionicsubstance B; supplying the treatment liquid to an inlet of a membraneexchanger; removing a spent liquid from an outlet of the membraneexchanger; measuring the concentration of the second ionic substance Bin the treatment liquid; and measuring the concentration of the secondionic substance B in the spent liquid, wherein the injection flowratesQ1 and Q2 are regulated on the basis of the concentrations of the secondionic substance B measured in the treatment liquid and in the spentliquid.
 2. Method according to claim 1, characterized in that theinjection flowrates Q1 and Q2 are regulated on the basis of a differencebetween the concentrations of the second ionic substance B measured inthe treatment liquid and in the spent liquid.
 3. Method according toclaim 2, characterized in that the injection flowrates Q1 and Q2 areregulated in such a way that the difference between the concentrationsof the second ionic substance B measured in the treatment liquid and inthe spent liquid remains substantially equal to a given value.
 4. Methodaccording to claim 1, characterized in that the first ionic substance Ahas, in the second concentrated solution, a same concentration as in thefirst concentrated solution.
 5. Method according to claim 1, furthercomprising the step of infusing a patient with a third solutioncontaining at least a third ionic substance C absent from the treatmentliquid.
 6. Method according to claim 5, characterized in that the thirdionic substance C is bicarbonate.
 7. System for extracorporeal treatmentof blood, comprising: a device for preparing a treatment liquid from aliquid, such as water, and two concentrated solutions, comprising: apreparation conduit with a first end intended to be connected to asource of liquid, such as water, and a second end for delivering atreatment liquid, first injection means for injecting into thepreparation conduit, at a flowrate Q1, a first concentrated solutioncontaining at least a first ionic substance A and a second ionicsubstance B, the second ionic substance B having, respectively, in thefirst concentrated solution, a first concentration, second injectionmeans for injecting into the preparation conduit, at a flowrate Q2, asecond concentrated solution containing at least the first ionicsubstance A, the second ionic substance B having, in the secondconcentrated solution, a second concentration different than the firstconcentration in the first concentrated solution, and means forregulating the first and second injection means and for adjusting theinjection flowrate Q1 of the first concentrated solution and theinjection flowrate Q2 of the second concentrated solution in such a waythat at any given time the diluted solution resulting from the mixing ofthe liquid and the concentrated solutions has a desired concentration ofthe first substance A and a desired concentration of the secondsubstance B; a supply conduit for supply of treatment liquid, forconnecting the preparation conduit of the treatment device to an inletof a membrane exchanger; a removal conduit for removing spent liquid,intended to be connected to an outlet of the membrane exchanger; a firstdevice for measuring the concentration of the second ionic substance Bin the treatment liquid, arranged on the preparation conduit; and asecond device for measuring the concentration of the second ionicsubstance B in the spent liquid, arranged on the removal conduit,wherein the regulating means is provided for regulating at least one ofthe first and second injection means on the basis of informationsupplied by the first and second devices for measuring the concentrationof the second ionic substance B.
 8. Treatment system according to claim7, characterized in that the first ionic substance A has, in the secondconcentrated solution, a same concentration as in the first concentratedsolution.
 9. Treatment system according to claim 8, characterized inthat the two said concentrated solutions are identical to each otherexcept that the concentration of the second ionic substance B differsfrom one solution to the other.
 10. Treatment system according to claim7, characterized in that the regulating means is provided for varyingover the course of time at least one of the injection flowrate Q1 andthe injection flowrate Q2 of the concentrated solutions A and B in sucha way that the concentration of the second substance B in the dilutedsolution varies over the course of time in accordance with apredetermined profile.
 11. Treatment system according to claim 7,characterized in that the regulating means is provided for varying overthe course of time at least one of the injection flowrate Q1 and theinjection flowrate Q2 of the concentrated solutions A and B in such away that the concentration of the first substance A in the dilutedsolution varies over the course of time in accordance with apredetermined profile.
 12. Treatment system according to claim 7,characterized in that the regulating means is provided for maintainingconstant the sum of the injection flowrates Q1+Q2 of the concentratedsolutions A and B, in such a way that, for a constant flowrate Q0 of theliquid in the conduit, the concentration of the first substance A in thediluted solution remains substantially constant.
 13. Treatment systemaccording to claim 7, further comprising means for infusing a patientwith a third solution containing at least one ionic substance C absentfrom the treatment liquid.
 14. Treatment system according to claim 13,charaterized in that the substance C is bicarbonate.